Uterine leiomyomas (fibroids) are the leading indication for hysterectomy in the United States. Despite the morbidity and high medical costs associated with fibroids, there has been little epidemiologic study of this condition in the United States. Uterine leiomyomas are histologically identifiable as benign smooth muscle tumors with varying amounts of associated fibrous tissue. Many women have more than one uterine leiomyoma, but each appears to be clonally distinct. Several specific cytogenetic changes have been identified in tumor tissue, but most show no chromosomal abnormalities. These benign tumors are hormone-dependent. They develop after puberty and regress after menopause. Both estrogen and progesterone are considered important stimulants, or at least permissive factors for tumor growth. To address the research needs in this field we have designed four studies. The first is a large epidemiologic study, the NIEHS Uterine Fibroid Study, designed to 1) estimate the age-specific cumulative incidence of leiomyomas in black and white women, aged 35-49, 2) identify risk factors for the condition, 3) compare growth mediating factors in tumor and matching myometrial tissues collected at time of hysterectomy, and 4) to identify factors associated with development of fibroid symptoms including pelvic pain and uterine bleeding. The second study (Fibroid Growth Study, Shyamal Peddada, PI) is a clinical study of fibroids designed to describe fibroid growth and compare the growth-mediating factors in growing vs nongrowing tumors. The third study, Postpartum Uterine Regression, monitors fibroid change with pregnancy and postpartum uterine regression. The fourth study, a prospective study of fibroid incidence, is currently under development. In this study we will enroll women before they have fibroids and follow them over 5 years for fibroid incidence. After estimating the age-specific incidence of uterine fibroids for black and white women, we began to examine risk factors for uterine fibroids. Pregnancy is protective, though not those that occur before the mid twenties. Alcohol appears to increase risk. In two cases we have replicated findings from animal models of fibroids. We find that the location of fibroids is somewhat different for parous and nonpauous women, and that prenatal exposure to DES is associated with increased development of fibroids. Increasing LH is associated with increased prevalence of the tumors, though LH may not be having direct proliferative effects, as we had hypothesized. We find no evidence for increased risk of fibroids with oral contraceptive use or with variability in menstrual-cycle length. We also explored our data on body fat and exercise. We find a small increase in risk with increased BMI (similar to other studies), and we also find that exercise is protective. As in the recent cohort analyses, smoking was not associated with risk in our data. We also collected questionnaire data for exploratory analyses on early-life exposures and several environmental/occupational exposures. While few factors showed associations with fibroid development, we did find an association of childhood use of insect repellent with fibroids. This may merit further investigation given the possible link between insect repellents and breast cancer. We measured fasting insulin and IGF-I in blood specimens collected from participants, hypothesizing both would be risk factors for fibroids. Surprisingly both tended to be protective, and diabetics were actually significantly less likely to have fibroids. We examined vitamin D status in relation to prevalence of fibroids both with the biomarker of hydroxylated vitamin D and with questionnaire data on time outside. With both methods, women with low vitamin D status had higher fibroid prevalence, and the findings were consistent for blacks and whites. We are beginning to examine dietary factors that may be related to fibroids. Regardiing fibroid symptoms, we found that urinary incontinence was significantly associated with fibroid size. We are currently examining the relationship between fibroid size and/or location and menstrual bleeding. The Fibroid Growth Study data have been analyzed and we conclude that: 1) spontaneous regression of fibroids occurs, 2) fibroids from the same woman grow at different rates, despite a uniform hormonal milieu, 3) fibroid size does not predict growth rate, and 4) age-related differences in fibroid growth between blacks and whites may contribute to the higher symptom burden for black women. We are currently examining short-term changes in growth of fibroids. In our study that monitored fibroid change during pregnancy and/or postpartum uterine regression we found that 36% of solitary fibroids were lost during the pregnancy/postpartum. Tumors that remained tended to have lost volume. We are now analyzing data to identify factors affecting the extent of fibroids reduction. We anticipate starting field work for the prospective study of fibroid incidence in spring of 2010.